A membrane protein called glucose transporter is required on the cell membrane to move glucose across the cell membrane from the outside into the inside, and vice versa.
The glucose transporter is divided into two major classes; one is a passive transporter or the facilitated diffusion-type glucose transporter (GLUT), and the other is an active transporter or the Na+/glucose transporter (SGLT), which transports glucose against its concentration gradient through the coupling with Na+ ion transport. There are 8 GLUT isoforms, which have a common structure having a molecular weight of about 50000 and 12 transmembrane spans.
SGLTs have a common structure having a molecular weight of about 75000 and 14 transmembrane spans.
The functions and expression sites of SGLTs 1 and 2 are outlined in Nippon Rinsho (Japanese Clinical) 55, extra number, Diabetes I, p. 59-64, 1997.
The human SGLT1 is expressed specifically in small intestine and kidney, and has a high affinity to glucose and a low transport activity, while the human SGLT2 is expressed specifically in kidney, and has a low affinity to glucose and a high transport activity. SGLTs have functions of absorbing glucose in small intestine and reabsorbing glucose in kidney, which has been excreted into the urine.
It is shown in a diabetes model rat that in consequence of inhibiting glucose reabsorption in kidney by inhibiting SGLT, glucose is excreted in the urine to decrease the blood glucose level (Diabetes 48: 1794-1800, 1999).
Until now, it has been considered that the passive transporter GLUT2 is primarily expressed in pancreatic beta cells and liver cells. GLUT2 is characterized by a low affinity to glucose and a high maximal transport activity. In pancreatic beta cells, GLUT2 is considered to take in glucose in a blood glucose level-dependent manner and function as glucose sensor along with glucokinase for the glucose level-dependent insulin secretion. In liver cells, GLUT2 is considered to function as glucose transporter to take blood glucose into the cells against the glucose concentration gradient across the cell membrane at high blood glucose level after a meal, and to release glucose into the bloodstream, which is produced intracelluarly through glycogenolysis or gluconeogenesis on an empty stomach.
It is reported that in samll intestine cells, human SGLT1 is moved from the cytoplasma to the cell membrane through the action of gastrointestinal hormone GLP-2, resulting in 3-fold increase in the glucose uptake activity (Am. J. Phsiol. 273, R1965-R1971, 1997).
The currently used insulin secretagogue (SU) closes KATP-channel in pancreatic beta cells to force the cells to secrete insulin irrespective of the blood glucose level. Accordingly, it is difficult to control the blood glucose level with SU, bringing about side effects, such as hypoglycemia, obesity through excessive insulin secretion. A phenomenon called secondary SU failure occurs, in which SU become ineffective after 10-year administration on average. This failure is considered due to fatigue of the pancreatic beta cells.
Therefore, it can be expected that activation of SGLT homolog function may enhance glucose uptake into pancreatic beta cells, and then the blood glucose-dependent insulin secretion. In addition, an activator of SGLT function is expected to cause no side effects, which the currently used insulin secretagogue (SU) shows.
In liver cells, GLUT2 releases glucose from liver into the bloodstream on an empty stomach, but a SGLT homolog is considered to enhance glucose uptake from blood into liver in spite of glucose concentration gradient across the cell membrane. Therefore, it can be expected to prevent glucose release from liver into blood, and thus a high blood glucose level on an empty stomach in a diabetes patient without occurrence of side effects such as hypoglycemia
Furthermore, an inhibitor of SGLT is capable of lowering blood glucose level by inhibiting glucose reabsorption in kidney, and thus is expected to prevent fat synthesis by reducing glucose uptake into liver.